Chronic heart failure is a major cardiovascular disease burden. Although coronary heart disease is the chief cause of chronic heart failure, drug therapies, especially anticancer drugs have been increasingly becoming a significant etiology. In this context, the anthracycline agent, doxorubicin (Dox) is one of the most important anticancer drugs with major clinical activity in a wide variety of cancers. The clinical use of Dox is severel limited by its cumulative dose-dependent cardiomyopathy, which is believed to occur via redox metal ion/free radical-mediated mechanisms. The iron-chelating agent, dexrazoxane is currently approved to prevent or reduce Dox-induced chronic heart failure (CHF) in women with metastatic breast cancer. Regardless of the use of dexrazoxane as well as Dox derivates, development of CHF remains a critical clinical problem in cancer patients treated with Dox. Hence, there is an urgent need to develop more effective strategies to protect against Dox-induced CHF without compromising its anticancer activity. Extensive studies show that the cancer therapeutic activity of Dox and its cardiotoxicity occur via distinct mechanisms. Therefore, it is likely to develop mechanistically-based strategies to selectively protect against Dox cardiotoxicity without compromising its anticancer activity. We propose the sustained coordinated upregulation of a wide spectrum of antioxidative/anti-inflammatory (AO/AI) enzymes in myocardium by long-term treatment with cruciferous 3H- 1,2-dithiole-3-thione (D3T) as a highly effective CAM strategy for protecting against Dox-induced CHF and potentiating its antitumor activity, and thereby enhancing the therapeutic efficacy of this widely used anticancer drug. To this end, in this R15 application we will investigate if the sustained coordinated upregulation of myocardial AO/AI enzymes by long-term D3T administration prevents or retards the development of Dox- induced CHF in a mouse model that closely mimics the situations in Dox-treated cancer patients. We will also investigate the role of Nrf2 signaling in the sustained coordinated upregulation of cardiac AO/AI enzymes by long-term treatment with D3T as well as the critical involvement of this signaling pathway in protecting against Dox-induced CHF. Finally, we will determine if this novel cruciferous dithiolethione-based cardioprotective modality potentiates Dox's antitumor activity in a mouse model of B16-F10 melanoma lung metastasis. In view of the crucial role of oxidative and inflammatory stress in heart failure of various etiologie, successful completion of this project will provide not only a novel strategy for protecting against Dox-induced CHF, but also an effective CAM modality for the intervention of CHF resulting from other causes, such as myocardial ischemia as well as other anticancer drugs. In this context, Dox is used as a common chemical model to create CHF for studying the molecular pathophysiology as well as cardioprotective strategies, including natural products.